The etiology of rheumatoid arthritis (RA), remains incompletely understood. It is considered to be a multifactorial disease, resulting from the interaction of both genetic and environmental factors. Epidemiologic research has produced convincing data for associations between environmental risk factors, including cigarette smoking, exogenous hormone use and female reproductive factors and RA susceptibility. Dietary studies suggest that high intake of certain antioxidants, fish, olive oil and cooked vegetables confer a protective effect against the development of RA, whereas red meat, fat, dairy and cereals may increase the risk of RA, although evidence for dietary etiology is inconclusive. However, the effect of individual food groups and nutrients may be too small to detect with limited sample sizes in previous studies. Overall dietary pattern and dietary quality analysis examines the cumulative effects of multiple nutrients, and may thus be more predictive of disease risk than individual foods or nutrients. To date, no studies have assessed the association between overall dietary patterns / dietary quality and RA risk, especially in the setting of a well-controlled large prospective cohort study. The goal of the proposed investigation is to address whether overall dietary patterns / dietary quality are associated with risk of RA in women using data from the largest rheumatic disease environmental epidemiology study in the world, the two Nurses' Health Study Cohorts (NHS I and NHS II). We will also examine the causal pathways between dietary patterns / dietary quality, biochemical measurements including plasma antioxidants and markers of inflammation, and risk of developing RA in a matched case-control subsample nested in NHS I and II cohorts. In addition, we will investigate possible interactions between dietary patterns / dietary quality and genetic factors in RA susceptibility. With recent advances in genetic epidemiology and high throughput genotying, the study of gene-diet interactions has become an exciting direction in the field of nutritional epidemiology. Overall, the large size of these cohorts, the prospective design, the repeated and detailed measurements of diet and covariates, the high follow-up rates, and the availability of biochemical measurements provide a unique opportunity to study the relationship between overall dietary patterns /dietary quality and risk of RA in an extremely cost-efficient manner. We believe that this project presents a novel approach to study diet-RA relationships and will have important public health implications. PUBLIC HEALTH RELEVANCE: The evidence for dietary etiology of RA is inconclusive. To date, no studies have assessed the association between overall dietary patterns / dietary quality, gene by dietary pattern interaction, and risk of RA. Findings from this large cohort study will furnish novel information about diet and etiology of RA, and have large potential public health implications for RA prevention.